COLUMBUS, Ohio-The combination
of capecitabine (Xeloda) and
weekly docetaxel (Taxotere) is well tolerated
and appears to produce higher response
rates in previously treated non-
small-cell lung cancer (NSCLC) patients
than docetaxel alone. Progression-free
survival using this combination regimen
appears similar to the docetaxel regimen.
Moreover, a preliminary finding that
merits further investigation suggests that
immunohistochemistry studies may predict
response to treatment.
"These results encourage further evaluation
of this regimen as a first-line treatment
in NSCLC," stated Tamila L. Kindwall-
Keller, DO, of Ohio State University,
Columbus, who reported these findings
(ASCO abstract 2601).
Capecitabine is a fluoropyrimidine that is converted to its active metabolite fluorouracil
(5-FU) by a three-step enzymatic
process. The final step of this process requires
thymidine phosphorylase (TP), a
potent tumor-associated, angiogenesis
factor. TP is expressed at higher levels in tumors than in normal tissue, allowing
for the preferential conversion of capecitabine
in neoplastic tissues. "Given the
prominent role of TP in the therapeutic
index of capecitabine-based treatment,
maximizing [tumor] TP activity would
result in an enhanced therapeutic index," Dr. Kindwall-Keller explained.
Earlier Phase I Study Shows
Efficacy and Safety
"Based on the preclinical observation
that TP is upregulated by docetaxel, we
conducted a phase I study of docetaxel in
combination with capecitabine," Dr.
Kindwall-Keller said. "The high and predictable
bioavailability of oral capecitabine
and the preferential conversion of
this tumor-targeted drug to 5-FU in neoplastic
tissues render capecitabine one of
the most interesting fluoropyrimidines in
clinical use."
According to the study's investigators,
TP is upregulated in cancer xenografts
after treatment with docetaxel, which explains
the prominent antitumor activity recently observed for the combination of
docetaxel and capecitabine. The phase I
study pursued the hypothesis that weekly
administration of docetaxel, as well as
capecitabine administration at times of
maximum TP upregulation, would enhance
the therapeutic index of this combination.
"In view of a preliminary finding of
efficacy and a good safety profile in the
phase I study, we decided to further evaluate
this regimen in previously treated
patients with NSCLC in the phase II
study," Dr. Kindwall-Keller said.
Outpatient Setting
In the phase II trial, treatment was
administered in an outpatient setting.
Docetaxel 36 mg/m2 was administered
intravenously weekly for 3 weeks (days 1,
8, and 15) of each 4-week period. Capecitabine
625 mg/m2 orally twice daily was
started on day 5 of every cycle and continued
for 14 days. Patients were instructed
to take 8 mg of oral dexamethasone 12
hours prior to the docetaxel infusion, immediately
prior to the docetaxel infusion,
and again 12 hours after the docetaxel
infusion on treatment weeks. Prophylactic
growth factor therapy (G-CSF, GMCSF,
and erythropoietic agents) was not
permitted.
Of the 39 eligible patients who enrolled
in the study, 36 were evaluable. All
patients had relapsed or refractory NSCLC
and had been previously treated with at
least one but not more than two platinum-
based or paclitaxel-based chemotherapy
regimens. To be eligible, patients
were required to have pathologically or
cytologically confirmed advanced NSCLC,
and could not have received cytotoxic
chemotherapy for at least 28 days prior to
starting this chemotherapy regimen. Patients
were also required to have an Eastern
Cooperative Oncology Group
(ECOG) performance status of 0, 1, or 2
and a predicted life expectancy of at least
12 weeks. Patients had to have adequate
organ function and no serious active infections,
and be free of another malignancy
for more than 5 years, with the exception
of basal cell or squamous cell skin
cancer or carcinoma in situ of the cervix.
Patients were excluded if they were
pregnant or were lactating, were less than
18 years of age, or had a known brain or
leptomeningeal disease, unless those lesions had no associated clinical symptoms
and had been previously irradiated.
Patients who had an acute myocardial
infarction within 6 months, congestive
heart failure requiring therapy, unstable
angina, uncontrolled diabetes mellitus defined
as a random blood sugar greater
than 250 mg/dL, or a baseline corrected
serum calcium greater than 11.5 mg/dL
were also excluded.
Overall Response 25%
A total of 39 patients (20 female, 19
male) were enrolled in the study. The
median age was 61. Twenty-five patients
(64%) had received one prior regimen,
and 14 (36%) had received two prior regimens.
Time to progression ranged from
1 to 13+ months. None of the 36 evaluable
patients experienced a complete response,
but 25% had partial responses, 3% had
minor responses, and 17% had stable
disease. The overall response rate was 25%
and the progression-free survival rate at
6 months was 19%. Median time to disease
progression was 53.5 days. Disease
progression was experienced by 56%.
Frequent grade 3/4 toxicity included
fatigue (22%), mucositis (17%), neutropenia
(14%), and thrombotic episodes
(9%). Eight patients required dose reductions
of capecitabine (one), docetaxel
(one), or both (six).
Dr. Kindwall-Keller concludes from
the study that the combination of docetaxel
and capecitabine appears to be well
tolerated with relatively little toxicity,
which is easily managed with dose modifications
and supportive care. The 6-
month progression-free survival rate with
the combination appears to be similar to
the rate seen with every 3-week dosing of
docetaxel. "The relatively high response
rate observed in this group of patients,
the majority of whom had received prior
taxanes, is encouraging and warrants evaluation
of this regimen as first-line treatment
in NSCLC," says Dr. Kindwall-
Keller.
The immunohistochemistry studies
suggest the possibility that thymidine
phosphorylase tumor/normal ratios by
cellular compartment may predict response
to treatment. Additional patients
are required to further investigate these
preliminary findings.

Your name

E-mail

The content of this field is kept private and will not be shown publicly.